Zinc Alleviated Imiquimod-induced Psoriasis In Mice

Psoriasis is one of the most prevalent skin diseases in adults.It is a chronic inflammatory disease with a long course and significantly recurrence trend.Clinically,the features of the disease include disfiguration and disability,chronicity,associated comorbidity and high prevalence.The main types of psoriasis include plaque psoriasis,pustular psoriasis,flexural psoriasis,guttate psoriasis and erythrodermic psoriasis.Plaque psoriasis is the most common type of psoriasis which accounts for about 90%of cases in hospital.The symptoms of this type of psoriasis are erythematous plaques covered with silver lamellar scales.This kind of plaques can extend on the large areas of patients’skin and easy to transfer the lesion site.This kind of disease is very similar to the pathological phenotype of mice with psoriasis induced by imiquimod,which the research focused on.Zinc ion,as an essential trace element,is abundant in the skin,especially in the epidermis,and plays an important role in the regulation of immune cell function,especially CD4"T helper cells.Zinc pyrithione has always been used as a component of dandruff shampoo due to its bactericidal effect,and pyrithione can be used as an ionophore to help ions pass through the phospholipid bilayer of the cell.Zinc gluconate has always been used as an ingredient for the treatment of dermatitis,and it is also one of the zinc ion supplements.It indicates that zinc may play a role in psoriasis.In order to verify the effect of zinc ion on mice with psoriasis induced by imiquimod,the psoriasis phenotype was induced by imiquimod on the nape of C57BL6mice.The features include visible erythema and covered silver scales,as well as skin thickening.Then,the mice were treated with different concentrations of zinc pyrithione,and the solvent was used as control.The clinical score of erythema,scaling,and thickening were significantly decreased in the group of 2%zinc pyrithione treatment compared to the control group.And the results of H&E staining showed that the epidermis of mice treated with 2%zinc pyrithione became thinner.Then,sodium pyrithione,which was the control group of pyrithione,zinc gluconate and zinc sulfate,which were the control groups of zinc ion,were used as control.The same concentration as 2%zinc pyrithione were used to treat the mice with psoriasis induced by imiquimod.It was found that compared to the control groups of sodium pyrithione and zinc sulfate,2%zinc pyrithione and 2%zinc gluconate could significantly reduce the clinical score of erythema,scaling,and thickening,and reduced the thickness of epidermis detected by H&E staining.We proved that zinc could alleviate imiquimod-induced psoriasis in mice,then we wanted to verify the pathway involved in zinc pyrithione regulating psoriasis mice induced by imiquimod.Zinc transporter pathway and TNFa/IL23/IL17/keratinocyte signaling pathway were detected.The results showed no difference of zinc transporter proteins after zinc treatment.The expression of IL17 on the other hand was significantly decreased after treated with zinc pyrithione,and the results of immunohistochemistry showed that the activation of CD4"T cell was significantly decreased after treated with zinc pyrithione.At the same time,IL17 pathway related factors and downstream keratinocyte differentiation and proliferation related factors were significantly decreased after zinc pyrithione treatment.Furthermore,q PCR,ELISA and Western blot analysis showed that the expression and release of IL23 decreased significantly after the treatment of zinc pyrithione.Since IL23 was mainly secreted by antigen-presenting dendritic cells in the process of skin inflammation,the treatment of dendritic cells with zinc pyrithione was detected.It was found that zinc pyrithione significantly decreased the secretion and release of IL-23 induced by imiquimod.We found three pathways which had been proved relating with IL-23 production and zinc may be involved.C/EBP beta,e IF2a and Myd88 were studied.Si RNA were used to knockdown the key factors of the three pathways,and then imiquimod was induced and zinc pyrithione was treated.We found that after C/EBP beta knockdown,zinc lost its function to decrease IL-23 production,which indicated that zinc pyrithione could affect the production and secretion of IL-23 by regulating the C/EBP beta pathway in dendritic cells.So far,we can draw a conclusion:Imiquimod treated on mouse epidermis,the molecules went through the epidermal layer and entered the dendritic cells,acted with TLR7 in the endosome of the cells and triggered downstream pathway,promoted the secretion of IL23,then activated IL23/IL17/keratinocyte pathway,triggered the pathogenesis of psoriasis.Zinc pyrithione treated to the psoriasis mice,the molecules went through the epidermal layer,and zinc ion entered the cell membrane of dendritic cells with the help of pyrithione,and entered the nucleus membrane.Then zinc ion combined with the transcription regulator C/EBP beta to inhibit the production and secretion of IL23,thereby inhibiting the downstream function of CD4~+T cells and IL17release,then inhibited the proliferation and differentiation of keratinocytes,attenuated the thickness of epidermis and reduced inflammation.Finally zinc ion significantly alleviated the pathogenesis of imiquimod-induced psoriasis in mice.This study showed that zinc ion could significantly alleviate pathogenesis of the psoriatic mice induced by imiquimod.Because the phenotypes of imiquimod-induced psoriatic mice are similar to the phenotypes of clinical plaque psoriasis patients,and zinc pyrithione has been used to act on the human body.The achievement of this research could be used in clinical application.Considering the clinical treatment of plaque psoriasis cost too much.Zinc ion cost much lower and can be used as a new clinical treatment option.